This proposal aims to apply comparative biology to the study of molecular genetic variation in diseases, caused by two fungal lung pathogens Coccidioides immitis and Histoplasma capsulatum, that pose severe clinical problem for HIV+ patients. This study is strongly influenced by reports last year of obtaining genes responsible for fungal disease and host resistance in plant systems. In these studies, prior knowledge of fungal genetic variation and host genetic variation were essential to success. In the long term, we hope that our data on pathogen and host genetic variation will make it attractive for medical mycologists to adopt the approaches developed by plant pathologists. Fungi. The part of this proposal devoted to fungi is made possible by our development of new methods to precisely define and analyze microbial nucleotide polymorphism. It is made timely by our discovery that Coccidioides immitis, long thought to be asexual, is recombining like a sexual organism in nature, and our demonstration that His to plasma capsulatum (already known to reproduce sexually in the lab) is likewise recombining in nature. The aims of this proposal are to: I) develop mating in C. immitis in the laboratory, 2) analyze genetic variation in C. immitis and H. capsulatum throughout North America, and 3) analyze genetic variation in C. immitis and H. capsulatum isolates taken from AIDS patients, from ethnic minorities known to be more susceptible to disseminated coccidioidomycosis, and from the environment. Host. The part of this proposal devoted to host genetic variation is made possible by advances in molecular characterization of the complex HLA locus in humans, and the observation that certain ethnic groups are an order-of-magnitude more likely to suffer disseminated coccidioidomycosis. The aim is to analyze HLA loci in Filipinos with disseminated coccidioidomycosis and compare these data with 500 haplotypes already determined for individuals in this ethnic group. Identification. Because we have new data for both fungi showing that isolates from different geographic locations are genetically isolated, we can design molecular identification systems to infer the geographic origin of clinical isolates. This information should be important to analyzing possible disease reactivation following HIV infection.